A single mutation in the acetylcholine receptor δ-subunit causes distinct effects in two types of neuromuscular synapses.

Mutations in AChR subunits, expressed as pentamers in neuromuscular junctions (NMJs), cause various types of congenital myasthenic syndromes. In AChR pentamers, the adult ε subunit gradually replaces the embryonic γ subunit as the animal develops. Because of this switch in subunit composition, mutations in specific subunits result in synaptic phenotypes that change with developmental age. However, a mutation in any AChR subunit is considered to affect the NMJs of all muscle fibers equally. Here, we report a zebrafish mutant of the AChR δ subunit that exhibits two distinct NMJ phenotypes specific to two muscle fiber types: slow or fast. Homozygous fish harboring a point mutation in the δ subunit form functional AChRs in slow muscles, whereas receptors in fast muscles are nonfunctional. To test the hypothesis that different subunit compositions in slow and fast muscles underlie distinct phenotypes, we examined the presence of ε/γ subunits in NMJs using specific antibodies. Both wild-type and mutant larvae lacked ε/γ subunits in slow muscle synapses. These findings in zebrafish suggest that some mutations in human congenital myasthenic syndromes may affect slow and fast muscle fibers differently.

Synaptic silencing of fast muscle is compensated by rewired innervation of slow muscle.

For decades, numerous studies have proposed that fast muscles contribute to quick movement, while slow muscles underlie locomotion requiring endurance. By generating mutant zebrafish whose fast muscles are synaptically silenced, we examined the contribution of fast muscles in both larval and adult zebrafish. In the larval stage, mutants lacked the characteristic startle response to tactile stimuli: bending of the trunk (C-bend) followed by robust forward propulsion. Unexpectedly, adult mutants with silenced fast muscles showed robust C-bends and forward propulsion upon stimulation. Retrograde labeling revealed that motor neurons genetically programmed to form synapses on fast muscles are instead rerouted and innervate slow muscles, which led to partial conversion of slow and intermediate muscles to fast muscles. Thus, extended silencing of fast muscle synapses changed motor neuron innervation and caused muscle cell type conversion, revealing an unexpected mechanism of locomotory adaptation.